We plan a multidisciplinary study of certain biochemical, physiologic and pathologic sequences involved in acute lung injury and repair. Complementary clinical and laboratory investigations of acute lung injury will: elucidate the initial causes and effects of pulmonary vascular injury during severe ARDS by using hemodynamic and radiologic studies as well as quantitative light microscopy and ultrastructural analysis, investigate connective tissue metabolism focusing on injured lung cell biology, study the interaction of the coagulation system with the acutely injured lung, and learn if prostaglandin metabolites mediate lung injury. We will use extracorporeal perfusion as a tool to study the normal and inflamed pulmonary circulation. We shall examine the nature and role of initial lung injury, platelet aggregation, in situ pulmonary thrombosis, vasospasm, and interstitial edema as causes of vascular obstruction in acute respiratory failure of diverse etiology. We will define the response of lung interstitial matrix to acute injury to learn its pivotal role in fibrosis and repair. In animal and clinical studies, we hope to modify this response by administering antifibrotic and antimitotic drugs. Since it may be central to several mechanisms, we will investigate prostaglandin precursor and derivative metabolism. We will use the membrane lung to study the pulmonary response to partial perfusion allowing safe lung lavage and thereby, directly delivering drugs to injured lung tissue.